Chronic myelomonocytic leukemia: natural history and prognostic determinants

A retrospective clinical review of 41 patients with chronic myelomonocytic leukemia revealed a median age of 66 years and a male:female ratio of 2.4:1. The disease was preceded by a myelodysplastic syndrome of a different subtype in 24% of the patients and transformed into acute leukemia in 24%. Splenomegaly was present in 54% of the patients and reached massive proportions in 24%. Chromosomal abnormalities occurred in 34% of those studied, most commonly in the younger age group; the most frequent were trisomy 8, monosomy 7, and deletions involving the long arms of chromosomes 20 and X. Polyclonal hypergammaglobulinemia was detected in 47% of the patients in whom serum protein electrophoresis was done. The median survival was 3 years. With use of univariate analysis, the statistically significant prognostic determinants were hemoglobin level, the "modified Bournemouth score," and bone marrow blast cell percentage. When these factors were subjected to a multivariate analysis, only bone marrow blast cell percentage was an independent prognostic determinant. Orally administered hydroxyurea controlled leukocytosis and splenomegaly in some patients without affecting the overall prognosis.     

60Coγ射线局部辐射后小鼠非辐射区域骨髓巨核细胞的变化

目的:临床局部辐射条件下会造成非辐射区域组织及细胞功能损害,最为突出的是对造血功能的影响。实验建立60Coγ射线左半身辐射动物模型,观察局部电离辐射对其非辐射区域骨髓巨核细胞的影响。方法:实验于2003-10/2005-03在解放军第三军医大学辐照中心和全军复合伤研究所完成。①实验动物:6～8周龄SPF级雄性昆明小鼠180只,随机数字表法分为正常对照组、全身辐射组、左半身辐射组、全身屏蔽辐射组,45只/组。②实验方法:全身辐射组小鼠固定于辐射架内;左半身辐射组小鼠麻醉后固定体位,用铅砖屏蔽右半身;全身屏蔽辐射组小鼠麻醉固定体位,用铅砖屏蔽全身。以60Coγ射线一次性辐射,剂量率68.46cGy/min。正常对照组不作任何干预。③实验评估:辐射后不同时相检测小鼠血清丙二醛含量及超氧化物歧化酶活性变化,计数外周血血小板,检测骨髓巨核祖细胞集落形成单位,观察骨髓组织病理改变及CD41a、CD61的表达。结果:全身辐射组第8天死亡2只,第9天死亡4只,其余各组无脱失。①外周血血小板计数:辐射后第2,7天,左半身辐射组外周血血小板数量显著低于正常对照组(P<0.01),但高于全身辐射组(P<0.01)。②血清丙二醛含量及超氧化物歧化酶活性变化:辐射后第2,9天,左半身辐射组血清丙二醛含量显著高于正常对照组(P<0.01),低于全身辐射组(P<0.01);血清超氧化物歧化酶活性显著低于正常对照组(P<0.01),高于全身辐射组(P<0.01)。③骨髓巨核祖细胞集落形成单位的变化:与正常对照组比较,辐射后6h左半身辐射组非辐射侧的巨核祖细胞集落形成单位显著降低(P<0.01),高于全身辐射组及左半身辐射组(P<0.01)。④骨髓组织病理改变:正常对照组有核细胞比例较高,分布均匀,并见多量散在分布的细胞龛;辐射2d后,左半身辐射组非辐射侧骨髓有核细胞较正常对照组减少,但好于全身辐射组、左半身辐射组。⑤骨髓CD41a及CD61表达的变化:辐射后2d与正常对照组比较,左半身辐射组非辐射侧骨髓CD41a及CD61阳性细胞数和相对荧光强度均显著降低(P<0.01),但高于全身辐射组、左半身辐射组(P<0.01)。结论:局部电离辐射作用后,可导致小鼠非辐射区域骨髓巨核细胞增殖能力降低,血小板减少,产生功能障碍。氧自由基激活可能参与了该损伤过程。     

Stage C prostatic adenocarcinoma: flow cytometric nuclear DNA ploidy analysis

Flow cytometric nuclear DNA ploidy analysis was used to study pathologic stage C prostatic adenocarcinoma (pT3, N0, M0) in 146 patients who underwent radical retropubic prostatectomy and bilateral pelvic lymphadenectomy between 1967 and 1981. Of these tumors, 46% had a DNA diploid pattern, 47% had a DNA tetraploid pattern, and 7% had a DNA aneuploid pattern. Abnormal ploidy patterns were associated more frequently with histologic high-grade tumors than with low-grade tumors. Considered alone, DNA ploidy pattern showed a strong association with subsequent prognosis. The median interval to progression for tumors with DNA tetraploid and DNA aneuploid patterns was 7.8 and 3.5 years, respectively. For the DNA diploid tumors, only 23% progressed within 18 years, the longest follow-up. At 10 years, only 10% of patients with DNA diploid tumors had died of prostatic cancer, in comparison with 28% of the DNA tetraploid and 36% of the DNA aneuploid groups (P less than 0.01). By analysis of a combination of histologic tumor grade and nuclear DNA ploidy pattern, an even stronger association with prognosis was demonstrated. For the 38 patients with histologic low-grade and DNA diploid tumors, progression-free survival was 92% at 10 years, in comparison with 57% for 23 patients with low-grade DNA nondiploid tumors. Patients with high-grade tumor had a poorer prognosis whether the DNA ploidy pattern was diploid or nondiploid. Nuclear DNA ploidy pattern is an important and independent prognostic variable for patients with pathologic stage C prostatic cancer treated by radical prostatectomy.     

Secular trends in hip fracture incidence and recurrence

Summary  The decline in hip fracture incidence is now accompanied by a further reduction in the likelihood of a recurrent hip fracture among survivors of the first fracture. Introduction  Hip fracture incidence is declining in North America, but trends in hip fracture recurrence have not been described. Methods  All hip fracture events among Olmsted County, Minnesota residents in 1980–2006 were identified. Secular trends were assessed using Poisson regression, and predictors of recurrence were evaluated with Andersen–Gill time-to-fracture regression models. Results  Altogether, 2,752 hip fractures (median age, 83 years; 76% female) were observed, including 311 recurrences. Between 1980 and 2006, the incidence of a first-ever hip fracture declined by 1.37%/year for women (p < 0.001) and 0.06%/year for men (p = 0.917). Among 2,434 residents with a first-ever hip fracture, the cumulative incidence of a second hip fracture after 10 years was 11% in women and 6% in men with death treated as a competing risk. Age and calendar year of fracture were independently associated with hip fracture recurrence. Accounting for the reduction in first-ever hip fracture rates over time, hip fracture recurrence appeared to decline after 1997. Conclusion  A recent reduction in hip fracture recurrence is somewhat greater than expected from the declining incidence of hip fractures generally. Additional research is needed to determine the extent to which this can be attributed to improved patient management.     

A crucial role for TNF-α in mediating neutrophil influx induced by endogenously generated or exogenous chemokines,KC/CXCL1 and LIX/CXCL5

Background and purpose:

Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP-2/CXCL2 and LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice.

Experimental approach:

Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)-α. Cytokine and chemokine levels were determined in peritoneal exudates and in supernatants of macrophages and mast cells by elisa. CXCR2 and intercellular adhesion molecule 1 (ICAM-1) expression was determined using immunohistochemistry and confocal microscopy.

Key results:

Antigen challenge induced dose- and time-dependent neutrophil recruitment and production of KC/CXCL1, LIX/CXCL5 and TNF-α, but not MIP-2/CXCL2, in peritoneal exudates. Neutrophil recruitment was inhibited by treatment with reparixin (CXCR1/2 antagonist), anti-KC/CXCL1, anti-LIX/CXCL5 or anti-TNF-α antibodies and in tumour necrosis factor receptor 1-deficient mice. Intraperitoneal injection of KC/CXCL1 and LIX/CXCL5 induced dose- and time-dependent neutrophil recruitment and TNF-α production, which were inhibited by reparixin or anti-TNF-α treatment. Macrophages and mast cells expressed CXCR2 receptors. Increased macrophage numbers enhanced, while cromolyn sodium (mast cell stabilizer) diminished, LIX/CXCL5-induced neutrophil recruitment. Macrophages and mast cells from immunized mice produced TNF-α upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM-1 on mesenteric vascular endothelium, which was inhibited by anti-TNF-α or anti-LIX/CXCL5.

Conclusion and implications:

Following antigen challenge, CXCR2 ligands are produced and act on macrophages and mast cells triggering the production of TNF-α, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM-1.     

The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD

Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end-stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (-1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%). CONCLUSION: a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients.     

Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study

OBJECTIVE: To determine the relationship between glucocorticoid exposure and cardiovascular (CV) events in patients with rheumatoid arthritis (RA). METHODS: A total of 603 adult residents of Rochester, Minnesota with incident RA between 1955 and 1995 were followed up through their medical records for a median of 13 years (total of 9,066 person-years). Glucocorticoid exposure was defined 3 ways: tertiles of cumulative exposure; recent use (< or =3 months) versus past use (>3 months); and average daily dosage (< or =7.5 mg/day or >7.5 mg/day). CV events, including myocardial infarction, heart failure, and death from CV causes, were defined according to validated criteria. Cox regression models were adjusted for demographic features, CV risk factors, and RA characteristics. RESULTS: Rheumatoid factor (RF)-negative patients with exposure to glucocorticoids were not at increased risk of CV events, irrespective of the glucocorticoid dosage or timing of use, as compared with the reference group of RF-negative patients who had never been exposed to glucocorticoids. In contrast, RF-positive patients were at increased risk of CV events, particularly with higher cumulative exposure, higher average daily dosage, and recent use of glucocorticoids. RF-positive patients with high cumulative exposure to glucocorticoids had a 3-fold increased risk of CV events (hazard ratio 3.06 [95% confidence interval 1.81-5.18]), whereas RF-negative patients with high cumulative exposure were not at increased risk (hazard ratio 0.85 [95% confidence interval 0.39-1.87]). CONCLUSION: RF-positive but not RF-negative patients were at increased risk of CV events following exposure to glucocorticoids. These findings suggest that glucocorticoids interact with RF status to modulate the occurrence of CV events in patients with RA. The mechanisms underlying this interaction are unknown and should be the subject of further research.     

Frozen Section Analysis for Intraoperative Margin Assessment During Breast-Conserving Surgery Results in Low Rates of Re-excision and Local Recurrence

Background Negative surgical margins minimize the risk of local recurrence after breast-conserving surgery. Intraoperative frozen section analysis (FSA) is one method for margin evaluation. We retrospectively analyzed records of patients who received breast-conserving therapy with intraoperative FSA of the lumpectomy cavity to assess re-excision rates and local control. Methods Records were retrospectively reviewed for individuals who underwent breast-conserving surgery for ductal carcinoma in situ (DCIS) or invasive carcinoma between 1993 and 2003. Inclusion criteria were a minimum of 2 years follow-up and intact tumor at the time of operation. The major outcome measure was local recurrence. The Kaplan-Meier test was used to evaluate local recurrence rates between groups. Results 290 subjects with an average age of 57.2 years (range 27–89) underwent 292 lumpectomies with FSA. 11.3% had DCIS, 73.3% had infiltrating ductal, 5.8% had infiltrating lobular, and 9.6% exhibited other forms of invasive carcinoma. 70 subjects underwent additional resection at the time of breast surgery, 16 underwent subsequent re-excision, and 17 underwent subsequent mastectomy. At a median follow-up of 53.4 months (range 5.8–137.8), there were six local recurrences (2.74%) in patients who had breast-conserving procedures and two local recurrences in patients who underwent mastectomy. There were no statistically significant associations among local recurrence rate, tumor size, nodal status, or overall stage. Local recurrences were higher in patients with DCIS compared with invasive carcinoma, and tumors >2cm. Conclusions Intraoperative FSA allows resection of suspicious or positive margins at the time of lumpectomy and results in low rates of local recurrence and re-excision. The low local recurrence rate reported here is comparable to those reported with other margin assessment techniques.